1. Field of the Invention
This invention relates to a method for calibration of instruments. More particularly, this invention relates to a method for calibration of instruments that monitor the concentration of a sterilant, e.g., hydrogen peroxide, in a system.
2. Discussion of the Art
Aseptic processing of consumable products, such as nutritional compounds and food products, is typically effected by separate sterilization of the products and the containers within which the products are packaged. Subsequent to sterilization, the sterilized products are placed in sterilized containers and sealed in a sterile environment for shipment, storage, and use.
Sterilization of such containers, which may include sterilization of separate closures as well, can be performed efficiently by use of a sterilant, such as hydrogen peroxide (H2O2) vapor, prior to the introduction of the desired sterilized products into the containers. In such a process, the containers are introduced into a sterilization apparatus in which the containers are flushed with hydrogen peroxide vapor. The containers are subsequently flushed with warm air or any other fluid suitable for achieving desirably low levels of residual hydrogen peroxide. This general procedure is highly effective in achieving sterilization of the containers and can be performed on any other articles that will come into contact with the material to be introduced into the containers.
Notwithstanding the effectiveness of sterilization by hydrogen peroxide, accurate monitoring of concentration levels of hydrogen peroxide vapor can be problematic. Problems in monitoring the concentration of hydrogen peroxide vapor result in part from changes in the physical and chemical properties of hydrogen peroxide vapor under processing conditions and the decomposition of hydrogen peroxide vapor upon contact with surfaces of various objects within the processing area. As such, undesired deviations of the concentration of hydrogen peroxide vapor from a process set point, along with excessive decomposition of hydrogen peroxide vapor, can result in loss of sterility of the containers and surrounding aseptic processing area. Moreover, hydrogen peroxide vapor is corrosive in nature, and thus excessive concentration levels of hydrogen peroxide may bring about detrimental effects to the equipment in and surrounding the processing area and surfaces of objects within the processing area. Furthermore, in accordance with government standards, subsequent use of sterilized containers requires low levels of residual sterilant.
Heretofore, detection systems for hydrogen peroxide vapor have been undesirably bulky, as exemplified by conventional near infrared (NIR) analysis apparatus. In addition, current off-line testing methods are typically too slow for monitoring levels of sterilant with sufficient accuracy. Previous arrangements have not allowed real time monitoring throughout an aseptic processing cycle, and in particular, have not been capable of monitoring concentrations of hydrogen peroxide vapor within the sterilization apparatus at select locations along the sterilant supply system during actual operations. However, U.S. Pat. No. 5,608,156 and Taizo et al., xe2x80x9cApplication of a Newly Developed Hydrogen Peroxide Vapor Phase Sensor to HPV Sterilizerxe2x80x9d, PDA Journal Of Pharmaceutical Science and Technology, Vol. 52, No. 1/January-February 1998, pp. 13-18, describe methods of detecting the concentration of hydrogen peroxide vapor and an apparatus therefor that appear to address some of the foregoing problems.
The concentration of sterilants detected within a system is generally a function of various environmental parameters, such as, for example, temperature, relative humidity, and various measurement conditions, such as, for example, proximate location of measurement. Conventional detection systems for sterilant typically cannot or do not account for fluctuations of environmental parameters and measurement conditions. However, such fluctuations can substantially affect the results of signal generation and data collection when commercially available sensors and equipment are used. It is therefore beneficial to maintain operating parameters proximate the location of measurement as uniform as possible during data collection.
U.S. Ser. No. 09/443,768, filed Nov. 9, 1999, entitled STERILANT MONITORING ASSEMBLY AND APPARATUS AND METHOD USING SAME, incorporated herein by reference, describes an integrated system for determining the concentration of hydrogen peroxide for aseptic process validation, control, and monitoring. This system is compact and can be used for on-line determination of the concentration of hydrogen peroxide. The system requires a unique calibration procedure at regular intervals to guarantee reliable and accurate test results. This system utilizes a sensor having elements made of SnO2. When SnO2 is heated to a high temperature, around 400xc2x0 C., in the absence of oxygen, free electrons flow easily through the grain boundary of the SnO2 particles. In clean air, oxygen, which traps free electrons by its electron affinity, is adsorbed onto the surface of the SnO2 particle, forming a potential barrier in the grain boundaries that restricts the flow of electrons, thereby causing the electronic resistance to increase. When the sensor is exposed to hydrogen peroxide vapor, SnO2 adsorbs its gas molecules and causes oxidation. This lowers the potential barrier, allowing electrons to flow more easily, thereby reducing the electrical resistance. Thus, the sensor uses an indirect method to measure the concentration of hydrogen peroxide vapor.
Voltage data from the output of the sensor must be compared to a database derived from a calibration process. The output of two different sensors cannot be compared directly without calibration. The calibration procedure uses several representative points (i.e., concentration at a given voltage) to establish a mathematical relationship that covers a specific test window. Only by means of calibration can the output voltage of a sensor be converted to a value of concentration.
Calibration procedures are important for minimizing deviations caused by such components as semiconductor chips, batteries, and signal conditioning circuits in a sensor in a portable detection system. Calibration procedures are important for minimizing deviations caused by such components as temperature and humidity compensation circuits, heating coils, data recording systems, and memory chips in a sensor in a fixed detection system.
If the calibration method is not reliable, the concentration of hydrogen peroxide vapor detected by a sensor might be misleading. In turn, an erroneous determination of the concentration of hydrogen peroxide vapor can bring about contamination in the operation system and result in spoilage. For example, a drop in voltage in the response of the sensor caused by an increase in the rate of flow of air may be interpreted as a decrease in the concentration of hydrogen peroxide vapor in the system. This apparent decrease may cause the controls in the system to increase the quantity of hydrogen peroxide delivered, thereby providing an excessive amount of hydrogen peroxide vapor. An excessive amount of hydrogen peroxide in the system may result in an excessive amount of residue. Conversely, an increase in voltage in the response of the sensor may result from a decrease in the rate of flow of air. If the delivery rate of hydrogen peroxide is correspondingly reduced, a breach in the sterility of the system may occur.
Calibration of sensors one at a time is inefficient, and, consequently, costly. It is well-known that no two sensors chosen at random are likely to be identical. Accordingly, it would be desirable to find way to calibrate individual sensors accurately and at reasonable cost. In addition, it would be desirable to find a way to calibrate individual sensors so that one or more of them could be used in portable units. The use of a greater number of portable units is desirable so that measurement of the concentration of hydrogen peroxide can be made at any point in a production line.
This invention provides a method and apparatus for calibrating a sensor for determination of the concentration of a sterilant, e.g., hydrogen peroxide vapor, in a sterilization system.
In one aspect, this invention provides a method for calibrating a sensor that is used for measuring the quantity of a sterilant in a system for delivering the sterilant, the method comprising the steps of:
(a) generating reference calibration data, the reference calibration data showing a mathematical relationship between a measurable parameter, e.g. voltage, and a quantity of the sterilant, e.g., parts of sterilant per million parts of air (ppm), for a plurality of sensors;
(b) generating sensor calibration data, the sensor calibration data showing a mathematical relationship between the measurable parameter and the quantity of the sterilant for an individual sensor; and
(c) normalizing the sensor calibration data to compensate for the difference between the measurable parameter for the reference calibration data and the measurable parameter for the sensor calibration data, whereby data obtained by the individual sensor can be used to accurately determine the quantity of sterilant in the system.
The reference calibration data can be generated by a method comprising the steps of:
(a) providing a plurality of sensors;
(b) subjecting each of the plurality of sensors to at least two quantities of air (e.g., 30 cubic meters/hour and 110 cubic meters/hour), each of the at least two quantities of air having (1) a known quality (e.g., 60% relative humidity at 70xc2x0 C.) and (2) a known concentration of sterilant vapor (e.g., 10,000 ppm of hydrogen peroxide vapor), the sterilant vapor having a known physical condition (e.g., 70xc2x0 C.);
(c) measuring the signals (e.g.; voltage) emitted by each of the plurality of sensors, each of the signals being proportional to a concentration (e.g., ppm) of sterilant vapor;
(d) establishing a mathematical relationship between the signals emitted by each of the plurality of sensors and the concentrations of sterilant vapor for each of the plurality of sensors; and
(e) establishing the reference calibration data by means of a statistical analysis of the signals emitted by each of the plurality of sensors and the concentrations of sterilant vapor for each of the plurality of sensors.
The sensor calibration data can be generated by a method comprising the steps of:
(a) providing a sensor;
(b) subjecting the sensor to at least two quantities of air, each of the at least two quantities of air having (1) a known quality and (2) a known concentration of sterilant vapor, the sterilant vapor having a known physical condition;
(c) measuring the signals (e.g., voltage) emitted by the sensor, each of the signals corresponding to a concentration of sterilant vapor (e.g., ppm of hydrogen peroxide vapor); and
(d) establishing a mathematical relationship between the signals emitted and the concentrations of sterilant vapor for the sensor.
The sensor calibration data can be normalized to compensate for the difference between the measurable parameter for the reference calibration data (e.g., voltage) and the measurable parameter for said sensor calibration data for the sensor (e.g., voltage) by a method comprising the steps of:
(a) selecting a concentration of sterilant vapor;
(b) determining the value of the measurable parameter at which the concentration of the sterilant vapor obtained from the sensor calibration data equals the concentration of said sterilant vapor obtained from the reference calibration data; and
(c) adjusting the values measured by the individual sensor a sufficient amount to compensate for the deviation between the reference calibration data and the sensor calibration data.
The method of this invention brings about a reduction in the time required to calibrate a sterilization system and provides a means for directly comparing signals obtained from different sensors so that the complex steps involved in the indirect measurement of parameters are avoided.
In one embodiment, which is relatively simple to implement, a linear relationship between the measured signal (e.g., voltage) and the concentration of sterilant (e.g., ppm of hydrogen peroxide vapor) is assumed. Points on the curve for an individual sensor (i.e., sensor calibration data) are moved either vertically or rotationally or both in order to convert the values of concentration associated with that point to a value of concentration on the curve representing the reference calibration data.
The form of the data for calibration of sensors for determining the concentration of hydrogen peroxide vapor in a stream of air is not critical. Preferred forms for presentation of data include, but are not limited to, curves plotted on Cartesian coordinates, nomograms, and look-up tables containing signal/concentration data.
In one embodiment, in which curves plotted on Cartesian coordinates are employed, the method involves the steps of
(a) preparing a reference calibration curve, the reference calibration curve having a slope and an intercept;
(b) preparing a sensor calibration curve, the sensor calibration curve having a slope and an intercept; and
(c) normalizing the sensor calibration curve to compensate for (1) the difference between the slope of the reference calibration curve and the slope of the sensor calibration curve and (2) the difference between the intercept of the reference calibration curve and the intercept of the sensor calibration curve.
For this embodiment, the reference calibration curve is prepared by a method comprising the steps of:
(a) providing a plurality of sensors;
(b) subjecting each sensor of the plurality of sensors to at least two quantities of air, each of the at least two quantities of air having (i) a known quality and (ii) a known concentration of sterilant vapor, the sterilant vapor having a known physical condition;
(c) measuring the signals emitted by each of the plurality of sensors, each of the signals being proportional to the concentration of sterilant vapor;
(d) establishing a linear mathematical relationship between the signals emitted by each of the plurality of sensors and the concentrations of sterilant vapor for each of the plurality of sensors; and
(e) establishing the reference calibration curve by means of a statistical analysis of the signals emitted by each of the plurality of sensors and the concentrations of sterilant vapor for each of the plurality of sensors.
For this embodiment, the sensor calibration curve is prepared by a method comprising the steps of:
(a) providing an individual sensor;
(b) subjecting the sensor to at least two quantities of air, each of the at least two quantities of air having (1) a known quality and (2) a known concentration of sterilant vapor, the sterilant vapor having a known physical condition;
(c) measuring the signals emitted by the sensor, each of the signals being proportional to the concentration of sterilant vapor; and
(d) establishing a linear mathematical relationship between the signals emitted by the individual sensor and the concentrations of sterilant vapor for the individual sensor.
The sensor calibration curve is normalized to compensate for (1) the difference between the slope of the reference calibration curve and the slope of the sensor calibration curve and (2) the difference between the intercept of the reference calibration curve and the intercept of the sensor calibration curve by a method comprising the steps of:
(a) determining the intercept of the reference calibration curve;
(b) determining the intercept of the sensor calibration curve;
(c) determining the slope of the reference calibration curve,
(d) determining the slope of the sensor calibration curve;
(e) adjusting the sensor calibration curve, if necessary, in order to compensate for the difference between the intercept of the reference calibration curve and the intercept of the sensor calibration curve; and
(g) adjusting the sensor calibration curve, if necessary, in order to compensate for the difference between the slope of the reference calibration curve and the slope of the sensor calibration curve.
In another aspect, this invention provides a method for calibrating a portable unit for measuring the concentration of hydrogen peroxide. In this method, hydrogen peroxide vapor can be passed through a calibration vessel, which is submerged in a water bath, under controlled testing conditions. A portable sensor for the detection of hydrogen peroxide vapor installed within the calibration vessel will respond to the concentration of hydrogen peroxide, the temperature, and the relative humidity for each test run. The concentration of hydrogen peroxide can be rechecked by a standard titration method. The accuracy of the value of the concentration of hydrogen peroxide thus determined can be checked by means of a detection unit for hydrogen peroxide vapor residue (Drager kit) to determine the concentration of residual hydrogen peroxide in the flow stream exiting the system. Additional impingers can be added to the system to capture all hydrogen peroxide from the stream of flowing air if residual hydrogen peroxide should be detected by a detection unit for hydrogen peroxide vapor residue. Additional data can be generated to cover those conditions that would be expected to be encountered in a practical application.
The method of this invention is capable of conducting calibrations that mimic both static and dynamic processing conditions, such as seen in sterilization of Bosch aseptic machines and hydrogen peroxide spray sterilization of bottles. Flexibility in the selection of parameters encountered in the generation of hydrogen peroxide vapor allows dynamic and static calibration of instruments for the determination of the concentration of hydrogen peroxide under conditions of high temperature, high concentration, variable rate of flow of air, and variable humidity for the test cell.
The method of this invention allows the calibration of instruments for determining the concentration of hydrogen peroxide vapor for numerous applications. The combined application of a water bath, a titration station, a Drager kit, a metering pump, and a hydrogen peroxide flow meter allows calibration of a portable detection unit for the determination of low concentrations of hydrogen peroxide.
The method of this invention can also be used to investigate the condensation of hydrogen peroxide by changing the rate of injection of hydrogen peroxide, the temperature(s) of the heat exchanger(s), the temperature(s) of the water bath(s), and the rates of flow of air. The rates of condensation and decomposition of hydrogen peroxide can be calculated by determining the difference between the amount of hydrogen peroxide injected and the amount of hydrogen peroxide detected over a selected period of time. The temperature at which air can be saturated by hydrogen peroxide under known conditions can be estimated as well.
The method of this invention can be used to calibrate a sensor for a sterilization system to improve the ability to determine the concentration of sterilant at a given point in the system at any time at various processing stages. By this method, accurate information on the process at each stage can be provided.
The method of this invention can also be used to calibrate instruments for monitoring the concentration of hydrogen peroxide vapor in any environment where hydrogen peroxide vapor is employed. Such environments include, but are not limited to, clean room operations, pharmaceutical isolator sterilization, aseptic processing systems, and microbiological investigation of death rate for various bacteria under the effect of hydrogen peroxide.
This invention provides a method for calibrating instruments for determining the concentration of a sterilant, e.g., hydrogen peroxide vapor, for a wide range of processing and operating conditions. These operating condition include, but are not limited to, air temperature, flow rate of air, evaporation temperature, hydrogen peroxide injection rate, degree of saturation of air by hydrogen peroxide vapor at different temperatures, humidity variations, pressure fluctuations, etc.
It is to be understood that the method of this invention is not limited to the sterilant hydrogen peroxide. The method of this invention can be used to calibrate instruments for determining the concentration of other gases used for sterilization.